It is well known that as individuals age the rate of epidermal cell replication and desquamation, i.e. turnover of cells, decreases or the epidermis becomes senescent, this frequently produces a dull, aged appearance. In addition, the vascularity of skin decreases with time and the underlying collagenous framework undergoes structural fragmentation secondary to aging and photo-damage, hence elastosis; as a result, wrinkles and sagging occur.
"Senescence" at the cellular level results from inadequate DNA repair leading to disordered and/or nonexistent cell replication. Loss of mitotic control factors in the nucleus and cytoplasm including disordered nuclear cytoplasmic exchange and permanent closing of microcirculatory capillary beds results in focal cell dropout and loss of cell and organelle membrane function.
The lifetime effects of the damage include wrinkling and hardening of the skin with age. The skin is made up of supportive material, including elastin and collagen. Collagen is a major protein component of the white fibers of connective tissue, such as cartilage and bone. White elastin is the major protein in the connective tissue of large blood vessels in the skin which enables these tissues to stretch and resume their original confirmation. Both collagen and elastin contain fibers that are linked together with imide bonds. It is believed that mammalian or human aging involves the oxidation of imide bonds to amide bonds with decreased elastic and flexible properties. A free radical mechanism is involved in wrinkling of the skin and results from the negative effects oxidation products which causes tissue aging.
A prospective randomized double blinded clinical trial using skin graft donor sites to determine whether recombinant epidermal growth factor (EGF) would accelerate the rate of epidermal cell regeneration in humans was conducted as described in Brown, et al., "Enhancement of Wound Healing by Epidermal Growth Factor: An Initial Clinical Report," New England Journal of Medicine, 321:76-79 (1989). Epidermal growth factor (EGF) was evaluated for its effect on topical treatment of healing chronic wounds in a prospective open label cross over trial as described in Brown, et al., "Stimulation of Healing of Chronic Wounds by Epidermal Growth Factor," Plastic & Reconstructive Surgery, 88:189 (1991)
U.S. Pat. No. 4,695,590 describes a method for retarding aging by administering synthetic chemicals, such as certain hydroxy diphenyl alkyl derivatives, preferably by oral administration. It would be desirable to avoid the internal administration of synthetic chemicals both for convenience and to avoid possible side effects of internally administered synthetic chemicals.
A variety of protein factors are known to be essential to the growth and differentiation of cells including epidermal cells. Many of these proteins extracted from tissues have been identified: such as epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and the like. U.S. Pat. No. 4,959,353 describes the use of epidermal growth factor for treating corneal wounds and U.S. Pat. No. 5,130,298 describes compositions of epidermal growth factor stabilized against degradation with metal cations and used for treating wounds. U.S. Pat. No. 5,104,977 discloses use of TGF-beta with either TGF-alpha for treating damaged tissue. However, as these patents illustrate, protein growth factors have not been previously shown to decrease epidermal cell senescence in unabraded or nonwounded skin. It had been previously thought that large proteins such as growth factors could not penetrate uninjured or intact skin in order to reach the appropriate basal cell layers to increase cellular replication and thereby decrease epidermal cell senescence.
It would be desirable to have a simple method to decrease epidermal cell and thereby cutaneous senescence in humans with or without aesthetic and reconstructive surgery.